Mallhi et al.

BMC Infectious Diseases (2015) 15:399

DOI 10.1186/s12879-015-1141-3

RESEARCH ARTICLE Open Access

Clinico-laboratory spectrum of dengue viral

infection and risk factors associated with
dengue hemorrhagic fever: a retrospective
study
Tauqeer Hussain Mallhi1,2*, Amer Hayat Khan1,2, Azreen Syazril Adnan2, Azmi Sarriff1, Yusra Habib Khan1,2
and Fauziah Jummaat3

Abstract
Background: The incidence of dengue is rising steadily in Malaysia since the first major outbreak in 1973. Despite
aggressive measures taken by the relevant authorities, Malaysia is still facing worsening dengue crisis over the past
few years. There is an urgent need to evaluate dengue cases for better understanding of clinic-laboratory spectrum
in order to combat this disease.
Methods: A retrospective analysis of dengue patients admitted to a tertiary care teaching hospital during the
period of six years (2008 – 2013) was performed. Patient’s demographics, clinical and laboratory findings were
recorded via structured data collection form. Patients were categorized into dengue fever (DF) and dengue
hemorrhagic fever (DHF). Appropriate statistical methods were used to compare these two groups in order to
determine difference in clinico-laboratory characteristics and to identify independent risk factors of DHF.
Results: A total 667 dengue patients (30.69 ± 16.13 years; Male: 56.7 %) were reviewed. Typical manifestations of
dengue like fever, myalgia, arthralgia, headache, vomiting, abdominal pain and skin rash were observed in more than
40 % patients. DHF was observed in 79 (11.8 %) cases. Skin rash, dehydration, shortness of breath, pleural effusion and
thick gall bladder were more significantly (P < 0.05) associated with DHF than DF. Multivariate regression analysis
demonstrated presence of age > 40 years (OR: 4.1, P < 0.001), secondary infection (OR: 2.7, P = 0.042), diabetes
mellitus (OR: 2.8, P = 0.041), lethargy (OR: 3.1, P = 0.005), thick gallbladder (OR: 1.7, P = 0.029) and delayed
hospitalization (OR: 2.3, P = 0.037) as independent predictors of DHF. Overall mortality was 1.2 % in our study.
Conclusions: Current study demonstrated that DF and DHF present significantly different clinico-laboratory
profile. Older age, secondary infection, diabetes mellitus, lethargy, thick gallbladder and delayed hospitalization
significantly predict DHF. Prior knowledge of expected clinical profile and predictors of DHF/DSS development
would provide information to identify individuals at higher risk and on the other hand, give sufficient time to
clinicians for reducing dengue related morbidity and mortality.
Keywords: Dengue, Dengue hemorrhagic fever, Dengue shock syndrome, Risk factors, Severe dengue

* Correspondence: tauqeer.hussain.mallhi@hotmail.com
1
Discipline of Clinical Pharmacy, School of Pharmaceutical Sciences,
University Sains Malaysia, Penang 11800, Malaysia
2
Chronic Kidney Disease Resource Centre, School of Medical Sciences, Health
Campus, University Sains Malaysia, Kubang Kerain 16150, Kelantan, Malaysia
Full list of author information is available at the end of the article

© 2015 Mallhi et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Mallhi et al. BMC Infectious Diseases (2015) 15:399
Background
Dengue viral infection (DVI) is a dangerous and debili-
tating disease. Alarmingly, 40 % of the world’s popula-
tion is living in the areas having a risk of being infected.
WHO estimates 50–100 million dengue cases with
approximately 22,000 deaths each year [1]. DVI has been
an important public health concern in Malaysia ever
since its first reported case in 1902 [2]. According to
ministry of health Malaysia, over the past few years there
is an increasing incidence of DVI with maximum num-
ber of cases observed in 2014 with a mortality rate of
0.2 % (Fig. 1). Sudden drop of dengue cases in 2011
(Fig. 1) might be attributed to the methodology differ-
ence in case reporting during this year [3].
The simultaneous presence of all four serotypes of
DVI in Malaysia makes this country ’hyperendemic” for
dengue [4]. Hot rainy weather, population growth, rapid
urbanization, rural–urban migration, inadequacies in
urban infrastructure including solid waste disposal,
mega-constructions, and rise in domestic and inter-
national travel are pivotal contributing factors for drastic
increase in dengue incidence in Malaysia [5].
Though mortality rate in dengue infection is not so
high (<1 % with adequate medical treatment) [1], but
costs associated with lost productivity and financial
burden of health services have large impact on econ-
omies and households. Suaya et al, estimated that the
annual cost of dengue illness (cost ± standard error) in
Malaysia is 42.2 ± 4.3 million US dollars. Infection with
dengue virus (DENV) appears to be a realistic threat to
travellers to Southeast Asia [6]. Increasing incidence of
dengue may forbid tourists to visit Malaysia that may
lead to economic crisis.
Several studies have demonstrated clinico-laboratory
spectrum of dengue in different regions [7–12]. Despite of
drastic increase in incidence of DVI in Malaysia, there
Fig. 1 Map of top five dengue hotspots in Malaysia in 2014 (1-Kelantan, 2-Perak, 3-Selangor, 4-Kuala Lumpur, 5-Johor) and Trend of Increasing
cases of dengue in Malaysia from 1998–2014
Page 2 of 12
is still paucity of data to understand its clinico-laboratory
spectrum. Few studies have been conducted in Malaysia
to explain clinical profile of dengue infection. These stud-
ies either have concise information [13, 14], small sample
size [15, 16] or included only specific population i.e. DHF,
fatal cases [17] and children [18]. Therefore there is an ur-
gent need to evaluate dengue cases more comprehensively
with larger patient’s pool. For this purpose, we conducted
a retrospective study in tertiary care hospital in Kelantan,
Malaysia (Fig. 1).
Methods
Ethics statement
Study was approved by Human Resource Ethics Com-
mittee (JEPeM) of HUSM (USM/JEPeM/14080278). All
data was analyzed anonymously and hence, informed
consent was not required. The patients were identified
from a central computerized record with their registra-
tion number (RN). Data of the cases were retrieved and
specific numeral codes were given to each case before
data analysis.
Study location and participants
Current study was conducted in Hospital University
Sains Malaysia (HUSM), tertiary level teaching hospital
with 950 beds that serves an estimated 1.4 to 1.8 million
inhabitants of Kelantan. Kelantan is an agrarian state
located in the north-east of Peninsular Malaysia and
among top five dengue hotspots in the country. Malays
are major (95 %) ethnic group in Kelantan while Chinese
constitutes merely 4 % of state population. Kelantan is
one of the major hotspots of DVI where dengue cases
till August 2014 (5367 case) have increased about 575 %
as compared to correspondent period in 2013 (575
cases) [19]. Drastic increase in dengue cases admitted to
HUSM during 2008–2014 were observed as compared
Mallhi et al. BMC Infectious Diseases (2015) 15:399
to 2001–2007 (1308 vs 2123, respectively). The hospital
also serves as referral centers for nearby states. Patients
without confirmed diagnosis, age >12 years, concurrent
co-infections (i.e. influenza, leptospirosis, malaria, typhus,
yellow fever, meningitis, viral hepatitis, rickettsia, rocky
mountain spotted fever and arenavirus infections) and
incomplete data were excluded from the study. All
suspected dengue cases admitted during Jan 2008 to Dec
2013 were taken into study but only confirmed cases
fulfilling inclusion criteria were subjected to analysis.
Dengue diagnosis, classification and laboratory tests
Suspected dengue infection was defined as the presence
of fever and any two of the following symptoms:
myalgia, headache, arthralgia, skin rash, retro-orbital
pain, hemorrhagic manifestation (s), or leucopenia
(white blood cell [WBC] count of <4 × 109 L − 1) [20].
Suspected cases were confirmed by using at least one of
the following criteria: (1) positive reverse transcriptase
polymerase chain reaction (RT-PCR) result, (2) presence
of dengue immunoglobulin M and G antibodies in acute
phase serum by enzyme linked immunosorbent assay
[Pan Bio Dengue IgM ELISA, Dengue IgM Dot Enzyme
Immunoassay, SD Dengue IgM and IgG capture ELISA
Kits; Standard Diagnostics, Korea], and (3) at least 4-fold
Fig. 2 Study flow diagram
Page 3 of 12
increase of dengue-specific hemagglutination inhibition
titers in convalescent serum when compared with acute
phase serum. The serum samples were also tested for
dengue-specific NS1 [pan-E Early dengue ELISA kit by
Panbio, Australia and Platelia dengue NS1Ag assay by
Bio-Rad Laboratories, USA) [21]. Only confirmed den-
gue cases were included in analysis. Primary dengue in-
fection was distinguished from secondary infection by
using IgM-IgG ratio where dengue infection was defined
as primary if ratio ≥ 1.8 and as secondary if < 1.8 [22] or
if there was a 4-fold increase of HAI and the titers
were ≤1:1280 and ≥1:2560, respectively [23]. Serologic-
ally confirmed dengue patients were subjected to clinical
case definition and disease severity was classified into
DF, DHF and DSS, according to the WHO criteria [20].
Patient’s demographics and clinical presentations were
recorded on day of admission while laboratory findings
were recorded for each day of hospitalization until dis-
charge. Study methodology with patient’s inclusion and
exclusion criteria are shown in Fig. 2.
Statistical analysis
Analysis was performed using SPSS software version
20.0.0. For the purpose of comparison patients were
divided into DF and DHF (including grade I to grade IV).
Mallhi et al. BMC Infectious Diseases (2015) 15:399
Categorical variables were recorded as frequencies and
percentages while continuous variables were recorded as
means and standard deviations (SD) unless otherwise
stated. Categorical and continuous variables were analyzed
using Chi-Square or Fischer-Exact test and independ-
ent t-test respectively. A logistic regression model was
performed to determine the factors independently
associated with severe form of dengue infection
(DHF). The variables with P values less than 0.25 in
univariate were considered as candidates for multivariate
analysis. The use of univariate P values <0.25 has advan-
tage of tending to include more variables in multivariate
analysis while traditional levels of P value such as 0.05 can
fail in identifying variables known to be important [24].
Receiver operating characteristics (ROC) curve analysis
was used to determine the area under the curve (AUC)
for prediction accuracy. Descriptive values below 5 %
(p < 0.05) were considered statistically significant.
Results
Out of total dengue cases admitted to hospital, 667
patients were included in analysis (Fig. 2). There was
approximately equal distribution of gender among
selected patients (male/female: 56.7 %/43.3 %, P = 0.062).
Fig. 3 (a) Dengue cases in different age groups (b) Days of illness prior to hospitalization (c) Duration of fever during hospitalization and (d)
Length of hospitalization among dengue patients
Page 4 of 12
Most of the patients (95.8 %) were adults (mean age:
30.68 ± 16.12 years) (Fig. 3a) with majority residing in
urban settings (60.4 %). Ethnic Malays were predomin-
ant with 90.6 % of total cases followed by Chinese (7.6),
Indians (1.5 %) and Thais (0.3 %).
Based on WHO criteria [20], DF was observed in
88.2 % (588/667) while DHF (grade I and II) and DSS
(DHF grade III & IV) were observed in 11.1 % (69/667)
and 0.7 % (10/667) cases, respectively. None of the
patients with DF and DHF progressed to severe disease
i.e. DHF and DSS respectively. Dengue infection risk
groups - including family history of dengue, living in
non-fogging zone, near stagnant water resources or near
construction sites and travelling to jungle or to areas
having high epidemics of dengue infection - were
assessed in all patients. Association of patients with risk
groups was observed in 40 % patients. Family history of
dengue was observed in 34 % cases while 23.5 % and
18.6 % patients were living near stagnant water resources
and constructions sites, respectively. Twenty seven (4 %)
cases were lived in areas where fogging was not done
prior to one month of their admission.
Tourniquet test (HESS test) was performed in 149
patients (positive: 101, negative: 48). Most of the patients
Mallhi et al. BMC Infectious Diseases (2015) 15:399
were presented with typical dengue complaints i.e. fever,
myalgia, arthralgia and headache (Table 1). Skin rash
(56.9 %), lethargy (39.2 %), rigors (35.4 %), dehydration
(25.3 %), shortness of breath (17.7 %), pleural effusion
(10.1 %), thick gall bladder (5.1 %) and hemorrhagic
anomalies (gingival bleeding, epistaxis, and hematemesis)
showed a high correspondence with DHF (P < 0.001) in
our study.
The mean value of serum creatinine (128.94 ±
81.20 μmol/L, P = 0.001), hematocrit (49.57 ± 6.22 %,
P < 0.001), aPTT (54.13 ± 7.81 s, P < 0.001) and PT
(13.84 ± 0.96 s, P < 0.001) were significantly higher
among DHF cases (Table 2).
Longer duration of hospitalization and prolonged fever
was observed in patients with DHF. Similarly, patients
with DHF admitted late to hospital than patients with
DF. We found that patients having age >40 years, urban
residency, secondary infection and warning signs were
more likely to have severe form of dengue infection
(DHF/DSS) (Table 3).
To identify possible risk factors of DHF among dengue
patients, logistic regression analysis was performed for
clinically relevant and statistically tested variables. Out of
five tested signs/symptoms, lethargy (OR: 3.1, P = 0.005)
and thick gallbladder (OR: 1.7, P = 0.029) were two symp-
toms with a higher likelihood of presenting DHF. Patients
with age greater than 40 years, secondary infection and
diabetes mellitus presented a higher risk of DHF in our
study (Table 4). It was also observed that patients who
were admitted after 3 days of onset of illness (delayed
hospitalization), were associated with a higher risk
(OR: 2.3, P = 0.037) of having DHF than patients who
were admitted within three days (Fig. 3b). ROC curve
analysis of logistic model is shown in Fig. 4.
Eight patients (1.2 %) died during study period (DF: 6,
DHF: 2). Age > 40 years, secondary infection and warn-
ing signs were observed in 6 (75 %), 3 (37.5 %), and 5
(62.5 %) fatal cases, respectively. All of the fatal cases in
our study were admitted on day 5 of onset of illness and
were accompanied by MODs. Shock (2/6), respiratory
failure (2/2) and renal complications (4/4) were primary
causes of death. Abnormal renal and hepatic anomalies
were observed in 12.1 % and 35.5 % of studied partici-
pants at discharge (Table 5).
Study limitations
Being a retrospective study, some limitations needed to
be addressed. All the reported values are dependent on
the thoroughness of clinician’s documentation. Clinical
outcomes of patients may be biased due to lack of stan-
dardized dengue management protocol, and the use of
different management strategies to treat DVI. Viral load
was not assessed in current study. Furthermore, patients
were not followed up to assess full recovery. Risk factors
Page 5 of 12
of mortality were not assessed because of few fatal cases
that negatively influence statistical power of current
study. However, the strength of the current study is
comprehensiveness, inclusion of patients during dengue
peak season (rainy season) and outbreaks.
Discussion
Current study is first comprehensive evaluation of DVI
in Kelantan, one of the major dengue hotspots in
Malaysia. Recent surge of DVI in Malaysia is the result
of change in variation of dengue virus (DENV). All four
serotypes of DENV are prevalent in Malaysia. Alarm-
ingly, discovery of fifth serotype (DENV-5) in Malaysia
demands more authoritative measures in terms of
surveillance, prevention and treatment [25]. We studied
DVI cases to understand clinico-laboratory characteris-
tics among multiethnic population of Malaysia.
Initially dengue infection was thought to be a disease
of children but recently it has been reported that age
distribution of this disease has shifted to adults and
older age [26, 27]. Increase mobility of adult population
in our society, better access to health care facilities and
ease of reporting to physicians might be some causative
factors of high incidence of DVI among adults. Similar
trend was observed in our study where prevalence of
dengue infection was higher among patients having age
20–40 years than patients with age <20 years (Fig. 4a).
In Malaysia, incidence of dengue among pediatric popu-
lation is declining while incidence among adult popula-
tion has been on the risk, as in 2006 about 80 %
reported cases to ministry of health had age > 15 years
[28]. The trend for increased incidence among adults
has important implications for control and prevention.
On the other hand, increasing age was also associated
with DHF in our study where patients with age > 40 years
were associated with four times odds of having DHF
(Table 4). It might be due to presence of secondary
infection that is believed to increase the risk of more
serious disease. In endemic areas, adults and older chil-
dren are likely to have past exposure to dengue infection
and also an increasing risk for secondary infection and
thus severe infection [22]. Out of 30 DHF patients with
age > 40 years, secondary infection was present in
approximately half of the cases. Additionally, generalized
decrease in immunity due to modified cellular and
humoral immune responses with increasing age might
be some other contributing factors of severe disease in
advance ages [29]. Furthermore, impact of age on
clinico-laboratory spectrum of disease has already been
reported [30]. In our study the patients with age 12–18
years had higher prevalence of cough, abdominal pain,
skin rash, gum bleeding, high fever, plasma leakage,
higher respiratory and heart rate as compared to patients
with age >18 years. These findings are consistent with
Mallhi et al. BMC Infectious Diseases (2015) 15:399 Page 6 of 12

Table 1 Clinical manifestations of dengue cases at presentation to hospital

Overall Cases (N = 667) n (%) DF (N = 588) n (%) DHF (N = 79) n (%) P–value
Commonly occurred (among >40 % population)
Fever 647 (97) 573 (94.7) 74 (93.7) 0.076*
Myalgia 483 (72.4) 419 (71.3) 64 (61) 0.069*
Arthralgia 389 (58.3) 336 (57.1) 53 (67) 0.092
Headache 385 (57.7) 344 (58.5) 41 (51.9) 0.265
Vomiting 368 (55.2) 318 (54.1) 50 (63.3) 0.122
Abdominal pain 299 (44.8) 264 (44.9) 35 (44.3) 0.921
Skin rash 294 (44.1) 249 (41.8) 45 (56.9) 0.014
Less Common (among 11 – 39 % population)
Diarrhea 225 (33.7) 194 (33) 31 (39.2) 0.270
Chills 224 (33.6) 199 (33.8) 25 (31.6) 0.698
Nausea 208 (31.2) 182 (31) 26 (32.9) 0.724
Anorexia 186 (27.9) 157 (26.7) 21 (26.6) 0.982
Lethargy 186 (27.9) 142 (24.1) 31 (39.2) 0.032
Retro-orbital pain 178 (26.7) 155 (26.4) 23 (29.1) 0.603
Rigors 172 (25.8) 144 (24.5) 28 (35.4) 0.037
Flushing 135 (20.2) 119 (20.2) 16 (20.3) 0.998
Cough 118 (17.7) 103 (17.5) 15 (19) 0.748
Restlessness 116 (17.4) 105 (17.9) 11 (13.,9) 0.387
Dizziness 110 (16.5) 99 (16.8) 11 (13.9) 0.512
Jaundice 87 (13) 74 (12.6) 13 (16.5) 0.337
Dehydration 78 (11.7) 58 (9.9) 20 (25.3) 0.007
Shortness of breath 73 (10.9) 59 (10) 14 (17.7) 0.040
Sore throat 76 (11.4) 64 (10.9) 12 (15.2) 0.258
Rare (among < 11 % population)
Malaise 52 (7.8) 45 (7.7) 7 (8.9) 0.707
Dysuria 29 (4.3) 22 (3.7) 7 (8.9) 0.069*
Hepatomegaly 39 (4.3) 25 (4.3) 4 (5.1) 0.740
Confusion 33 (4.9) 27 (4.6) 6 (7.6) 0.264*
Conjunctivitis 24 (3.6) 21 (3.6) 3 (3.8) 0.756
Chest pain 24 (3.6) 22 (3.7) 2 (2.5) >0.90*
Pleural effusion 23 (3.4) 15 (2.6) 8 (10.1) 0.003*
Ascites 15 (2.3) 15 (2.6) 4 (5.1) 0.266
Palpitation 14 (2.1) 14 (2.4) - -
Edema 14 (2.1) 12 (2) 2 (2.5) 0.677
Tachypnea 12 (1.8) 11 (1.9) 1 (1.3) >0.90
Splenomegaly 9 (1.3) 6 (1) 3 (3.8) 0.079
Thick gall bladder 9 (1.3) 5 (0.9) 4 (5.1) 0.014
Anasarca 8 (1.2) 6 (1) 2 (2.5) 0.243
Asthenia 8(1.2) 7 (1.2) 1 (1.3) >0.90
Convulsion 8 (1.2) 8 (1.4) 0 -
Tachycardia (0.6) 4 3 (0.5) 1 (1.3) >0.90
Hemorrhagic Manifestations
Petechia 80 (12) 68 (11.6) 12 (15.2) 0.352
Mallhi et al. BMC Infectious Diseases (2015) 15:399 Page 7 of 12

Table 1 Clinical manifestations of dengue cases at presentation to hospital (Continued)

Gingival bleeding 67 (10) 48 (8.2) 19 (24.1) < .001
Purpura/Ecchymosis 53 (7.9) 46 (7.8) 7 (8.9) 0.749
Epistaxis 35 (5.2) 19 (3.2) 16 (20.3) < .001*
Vaginal bleeding 24 (3.6) 21 (3.6) 3 (3.8) 0.756
Hematuria 18 (2.7) 17 (2.9) 1 (1.3) 0.711
Hematemesis 11 (1.6) 7 (1.2) 4 (5.1) < .001
Malena 4 (0.6) 0 4 (5.1) -
Blood in stool 4 (0.6) 3 (0.5) 1 (1.3) 0.397
Hemoptysis 2 (0.3) 2 (0.3) 0 -
*Fisher’s exact test (if more than 20 % of cells with expected counts of less than 5) while all the other P values were calculated by Pearson Chi-Square

previous studies [30, 31] and suggest presence of
varying clinical manifestations of dengue in different
age groups. Higher number of urban residents
(60.4 %) in our study might be due to location of
hospital surrounded by urban areas. Additionally,
urbanization also favors vector breeding. Males were
found to be affected by DVI slightly more than
females in our cohort, but this difference was not
statistically significant (P = 0.062). These findings are
consistent with results of Anker & Arima [32]. In
contrast, recently higher prevalence of DVI in female
has also been observed [33].
Since patients with mild or classical DF can develop
severe infection later, therefore it is important to look
for sings/symptoms to facilitate the early prediction of
severe dengue i.e. DHF/DSS. The clinical manifestations
might always offer the earliest marker in predicting
severe disease. Therefore dengue with warning signs
should be monitored vigilantly in order to avoid its
progression to severe disease [34]. Presence of warning

Table 2 Comparison of laboratory characteristics (on admission) of DF and DHF

Overall Cases (N = 667) Mean ± SD DF (N = 588) Mean ± SD DHF (N = 79) Mean ± SD P–value*
Age (Years) 30.69 ± 16.13 29.86 ± 15.67 36.80 ± 18.14 0.002
Temperature (°C) 37.68 ± 0.62 37.66 ± 0.61 37.78 ± 0.62 0.109
Pulse rate (BPM) 83.25 ± 17.57 83.30 ± 17.47 82.82 ± 18.36 0.820
Serum Creatinine (μmol/L) 99.13 ± 58.57 95.12 ± 53.58 128.94 ± 81.20 0.001
Total protein (g/L) 66.08 ± 12.02 66.40 ± 11.65 63.90 ± 14.180 0.157
Albumin (g/L) 40.26 ± 15.36 40.50 ± 16.29 38.61 ± 5.33 0.337
Globulin (g/L) 28.39 ± 5.35 28.48 ± 5.32 27.81 ± 5.51 0.318
AG ratio 1.79 ± 4.46 1.72 ± 3.91 2.29 ± 7.28 0.510
AST (IU/L) 152.42 ± 209.76 135.14 ± 184.53 185.03 ± 241.30 0.034
ALT (IU/L) 114.36 ± 166.64 113.31 ± 161.38 121.54 ± 200.13 0.743
ALP (IU/L) 105.85 ± 71.33 106.27 ± 70.99 102.92 ± 74.02 0.711
Total bilirubin (μmol/L) 12.29 ± 18.40 12.36 ± 19.32 11.77 ± 10.39 0.669
9
WBCs (cells × 10 /L) 5.16 ± 14.78 5.29 ± 15.73 4.17 ± 2.75 0.531
Thrombocytes (cells × 109/L) 97.59 ± 63.15 99.63 ± 65.56 82.74 ± 38.75 0.038
Hemoglobin (g/dL) 14.21 ± 7.98 14.18 ± 8.48 14.48 ± 1.52 0.750
Hematocrit (%) 41.10 ± 6.23 39.92 ± 5.25 49.57 ± 6.22 0.000
INR 1.06 ± 0.56 1.06 ± 0.60 1.04 ± 0.10 0.821
APTT (Sec) 43.62 ± 10.47 41.96 ± 9.86 54.13 ± 7.81 0.000
PT (Sec) 12.90 ± 1.37 12.84 ± 1.38 13.84 ± 0.96 0.000
Period of illness prior to hospitalization 4.16 ± 3.28 2.89 ± 1.84 4.45 ± 1.60 0.033
Duration of fever during hospitalization 4.21 ± 2.11 3.21 ± 2.60 4.60 ± 3.47 0.006
Length of Hospitalization (days) 4.88 ± 2.74 2.52 ± 1.92 4.64 ± 1.99 0.026
*Student t test or Mann–Whitney U test, where appropriate
Mallhi et al. BMC Infectious Diseases (2015) 15:399 Page 8 of 12

Table 3 Comparison of demographics and clinical features of DF and DHF

Overall Cases (N = 667) n (%) DF (N = 588) n (%) DHF (N = 79) n (%) P–value*
Age > 40 years 167 (25) 137 (23.3) 30 (38) 0.005
Male gender 378 (56.7) 326 (55.4) 52 (55.8) 0.08
Urban resident 403 (60.4) 346 (41.2) 57 (72.2) 0.023
o
Temperature > 38 C 229 (34.3) 197 (33.5) 32 (40.5) 0.218
Obesity 94 (14.1) 82 (13.2) 12 (15.2) 0.467
Co-morbidities
DM 36 (5.4) 13 (2.2) 23 (29.1) 0.001
HTN 35 (5.2) 17 (2.9) 18 (22.4) 0.021
CKD 33 (4.9) 26 (4.4) 7 (8.9) 0.085
IHD 25 (3.7) 19 (3.2) 6 (7.6) 0.178
CHF 2 (0.3) 2 (0.3) 0 (0) -
HPL 8 (1.2) 7 (1.2) 1 (1.3) 0.649
Risk group associationa 264 (39.6) 232 (39.5) 32 (40.5) 0.858
Secondary infection 73 (10.9) 58 (9.9) 18 (22.8) 0.015
Warning signs 271 (40.6) 224 (38.1) 47 (59.7) 0.000
Positive Hess test 101 (15.1) 85 (14.5) 16 (20.3) 0.177
Low MAP 37 (5.5) 34 (5.8) 3 (3.8) 0.469
Elevate Scr (AKI) 95 (14.2) 58 (9.9) 37 (65.8) 0.000
Thrombocytopenia 395 (59.2) 343 (58.3) 56 (70.8) 0.042
Leukopenia 363 (54.4) 321 (54.6) 42 (53.2) 0.596
Leukocytosis 36 (5.4) 32 (5.4) 4 (5.1) 0.842
Elevated ALT 362 (54.3) 315 (53.6) 47 (59.5) 0.321
Elevated AST 447 (67) 380 (64.6) 67 (84.8) 0.000
Elevated ALP 113 (19.9) 117 (19.9) 16 (20.3) 0.885
Transaminitis 360 (54) 311 (52.9) 49 (62) 0.125
Rhabdomyolosis 49 (7.3) 34 (5.8) 15 (19) 0.000
Multiple organ dysfunctions 138 (20.7) 97 (16.5) 43 (54.4) 0.000
Urinary sedimentations 96 (14.4) 78 (13.3) 18 (22.8) 0.034
Hemoconcentration 73 (10.9) 56 (9.5) 17 (21.5) 0.001
Prolonged PT and aPTT 116 (17.4) 93 (15.6) 23 (29.1) 0.003
Delayed Hospitalization (>3 days of onset of illness) 153 (22.9) 105 (17.9 %) 48 (60.8) 0.000
Death 8 (1.2) 6 (1) 2 (2.5) 0.243
*Chi-Square/Fisher’s Exact test, where appropriate, adefined as number of patients having association of dengue infection risk groups as described under
results section

signs was significantly associated with DHF in our study
(Table 3). According to logistic regression analysis, thick
gallbladder (OR: 1.7) and lethargy (OR: 3.1) were more
likely to be associated with DHF, while skin rash, retro-
orbital pain and rigors were not significant risk factors
(Table 4). Furthermore, dehydration, dyspnea, pleural
effusion, gingival bleeding, epistaxis and hematemesis
were more profound clinical presentations among DHF
patients (Table 1). These clinical presentations and
warning signs were not included in multivariate analysis
because they are significantly relevant with DHF and
were serve as diagnostic tool in clinical case definition of
dengue [20]. Similarly, presence of certain co-morbidities
like diabetes mellitus, hypertension, chronic kidney
disease, allergies, asthma, ischemic heart disease and
hepatic anomalies might place some patients at high
risk of developing DHF/DSS. We found statistical asso-
ciation of diabetes mellitus (DM) with DHF, where indi-
viduals suffering from DM had higher odds of
developing DHF than patients without disease. Hyper-
tension was more profound (P = 0.021) among DHF
cases (Table 3) but did not show any statistical associ-
ation with development of DHF, though unadjusted
estimates suggested that patients who had hypertension
Mallhi et al. BMC Infectious Diseases (2015) 15:399 Page 9 of 12

Table 4 Univariate and Multivariate logistic regression analysis for risk factors of DHF
Variables Univariate analysis Multivariate analysis
P-value OR 95 % CI P-value OR 95 % CI
Age > 40 years 0.005 2.0 1.23 – 3.31 <0.001 4.1 2.12 – 5.71
Secondary Infection 0.017 2.1 1.15 – 3.90 0.042 2.7 1.64 – 3.91
Diabetes mellitus 0.020 3.9 1.34 – 4.21 0.041 2.8 1.35 – 4.67
Hypertension 0.047 3.7 1.33 – 3.11 0.211 2.3 2.45 – 7.45
Skin rash 0.150 1.8 1.12 – 2.90 0.346 2.6 1.88 – 4.78
Lethargy 0.023 2.2 0.81 – 3.10 0.005 3.1 1.89 – 5.11
Retro-orbital Pain 0.604 1.2 0.68 – 1.93 - - -
Rigors 0.061 1.7 1.03 – 2.79 0.062 2.2 0.98 – 3.78
Thick gallbladder 0.007 6.2 1.63 – 23.67 0.029 1.7 0.78 – 2.12
Delayed hospitalization 0.008 2.7 1.88 – 4.11 0.037 2.3 1.34 – 2.89
Variables with P < 0.25 (retro-orbital pain) were excluded from multivariate analysis
Odds ratio (OR) and Confidence interval (CI) have been rounded off

were 1.7 times at higher risks of developing DHF
(Table 4). These findings are persistent with previous
literature [35, 36]. Increased capillary fragility and
permeability due to activation of T-lymphocytes and
release of cytokines in DM are might be some possible
factors of development of DHF [35, 36].
Approximately, 40 % patients in our study had risk
groups association (Table 3). These risk groups were
family history of dengue infection and living near
non-fogging zones, near stagnant water resources or
construction sites. These findings will aid health
authorities to initiate appropriate vector control mea-
sures in affected areas. Most of the dengue cases in
our study occurred during months of mid-November
to end of December. Heavy rain fall during these
Fig. 4 ROC Curve analysis of logistic regression model to predict DHF
months might be a contributing factor for increased
incidence of DVI. Preventive measures with full swing
should be carried out before these months in order to
combat this disease.
Fever among dengue patients typically lasts for 2–7
days. Total duration of fever in our study ranges from
1–8 days (Fig. 4c), among them prolonged fever was more
profound among DHF cases (mean 4.9 days, P < 0.006).
Longer duration of fever among dengue patients
ranges from 10–16 days has also been observed [8].
All the other possible causes of fever were ruled out
and no other cause was found. Fever was resolved
within 4 days of admission in most of the patients.
Prolonged fever was found to be associated with
longer hospital stay in our study. Average duration of
hospital stay was 4.88 days and DHF was associated
with significantly longer hospital stay (Table 2, Fig. 4d)
resulting in significant burden in terms of cost of
care. This is of particular importance in resource
limited setting, especially in dengue endemic regions.
Similarly, DF required hospital stay >3 days in our
study indicating that both DF and DHF impose a
considerable burden in the health care system.
Unusual manifestations of patients with severe organ
involvement such as liver, kidneys, brain or heart associ-
ated with dengue infection have been increasingly
reported in DHF and also in dengue patients who do not
have evidence of plasma leakage. In recent dengue clas-
sification, these manifestations are termed as “expanded
dengue syndrome” [20]. Liver was most affected organ
in our study and deranged hepatic enzymes were present
in most of the patients. Grossly elevated liver enzymes
are known to be associated with DHF and major bleed-
ing [16]. Mean levels of AST were significantly differing
between DF and DHF in our study (Table 2). Elevated
ALT and ALP was also observed in DHF patients, but
Mallhi et al. BMC Infectious Diseases (2015) 15:399
Table 5 Renal and Hepatic anomalies among dengue patients
at discharge
DF (N = 588) DHF (N = 79)
n (%) n (%)
Normal renal functions 522 (88.8) 64 (81)
Renal insufficiencies 61 (10.4) 14 (17.7)
(SCr <200 μmol/L)
Renal insufficiency 5 (0.9) 1 (1.3)
(SCr > 200 μmol/L)
Normal hepatic function 382 (65) 48 (60.8)
Mild to moderate transaminitis 175 (29.8) 27 (34.2)
(2–10 × ULN)
Severe transaminitis (>10 × ULN) 31 (5.3) 4 (5)
difference was not statistically significant (P > 0.05).
Additionally, hepatomegaly accounted 5.1 % and 4.3 %
among DHF and DF patients, respectively (Table 1).
Dengue virus (DENV) directly affects hepatocytes
(Kupffer cells) resulting in elevated liver transaminases
and hepatomegaly. Hepatocellular damage in dengue
infection is might be attributed to activated T – lympho-
cyte subsets, being more evident in DHF than in DF
[16]. Wahid et al. [16] demonstrated that extent of
hepatocellular damage can be predicted by spontaneous
bleeding, that was found in 9.7 % cases in our study. In
addition, hypoalbuminemia was more profound among
patients with DHF than with DF, though difference was
not statistically significant (Table 2). These results are
consistent with previous findings where hypoalbumin-
emia is often present in dengue infection [37, 38]. Our
results suggest that liver impairments are more common
in DHF compared to DF.
Kidney was second most affected organ after liver in
our study. Acute kidney injury (AKI) defined by AKIN
criteria was present in 14.2 % of total population and
was more commonly associated with DHF (Table 3).
Similarly, urinary sedimentations were found in 14.4 %
cases, more profoundly among DHF cases (Table 3). Sev-
eral reports have described that patients with DHF/DSS
are more likely to have AKI (Mallhi et al.) [39].
Spectrum of dengue induced nephropathies ranges from
proteinuria to severe AKI and can be explained by the
direct viral injury or antigen-antibody complex in glom-
eruli [40].
Dengue virus has broader tropism and can not only
replicate in hepatocytes and glomeruli but also in type II
pneumocytes, cardiac fibers, as well as in resident and
circulating monocytes/macrophages and endothelial cells
leading to multiple organ dysfunctions (MODs) [41].
MODs can be considered as a sequential or concomitant
occurrence of a significant derangement of function in
two or more organ systems of the body, against a back-
ground of a critical illness [42]. We used same criteria in
our study and found significantly higher prevalence of
Page 10 of 12
MODs (P < 0.001) among DHF cases than DF (54.4 % vs
16.5 %). Acute pancreatitis, type 1 respiratory failure,
circulatory failure and rhabdomyolosis were observed in
6 (1 %), 11 (1.6 %), 3 (0.4 %) and 49 (7.3 %) patients
respectively. MODs caused by bleeds into various organs
are also associated with higher mortality among DHF
patients [42]. In current study, MODs were observed in
all eight fatal cases where AKI was observed in 8, liver
failure in 4, pancreatitis in 4, respiratory failure in 2 and
circulatory failure in 2 patients.
Hematological profile of dengue patients is usually
served to differentiate DF and DHF [43]. Hematocrit has
been used as an important parameter in monitoring
patients with DF. According to Malaysian clinical prac-
tice guidelines [44], hematocrit values of 47 % for male
and 40 % for female were suggested for cut-off value
to suspect plasma leakage. These values were validated
in our study and we found hemoconcentration, charac-
terized by 20 % raised hematocrit, was significantly associ-
ated with DHF (Table 3). Similarly, thrombocytopenia was
more common among DHF patients and these findings are
consistent with previous reports [8, 13]. Hemoconcentra-
tion in our study might be due to dehydration and in-
creased vascular permeability [22]. However, reduction of
hematocrit levels to normal was more significant in DHF
than DF and it may be influenced by vigorous intravenous
therapy in DHF in current study. Besides these, simul-
taneous elevation of both PT and aPTT was more sig-
nificant among DHF (Table 3) and it can be attributed
to disturbance in balance of coagulation cascade path-
ways (prothrombotic, antithrombotic and fibrinolytic
pathways). Low levels of circulating protein C, S, anti-
thrombin III and elevated levels of tissue factor, throm-
bomodulin, PAI-1 are likely to be related to hemorrhage,
plasma leakage and shock in dengue infection [45].
Diagnostic delays may complicate clinical state of the
dengue patients [46]. On average the patients in current
study were admitted on day four of illness (Table 2) and
delayed hospitalization was found to be more common
among patients with DHF. These findings are consistent
with a Mexican study where diagnostic delay >2 days
was significantly associated with hemorrhagic cases [46].
A study in Cuba also reported that hospitalization of
patients at an average of 2.9 days was associated with
worsening clinical condition [47]. Late hospitalization
may also be a possible contributing factor of rapid
deterioration in severe dengue and our data clearly
demonstrated that patients with delayed hospitalization
had 2.3 times higher risks of developing DHF than those
who hospitalized within three days of onset of illness
(Table 4).
Dengue viral infections are rarely fatal, although fatal
infections do occur [38] due to plasma leakage, fluid accu-
mulation, respiratory distress, severe bleeding or multiple
Mallhi et al. BMC Infectious Diseases (2015) 15:399
organ involvement [41]. Overall mortality in our study was
1.2 % and all death cases had worst clinical presentations
and were accompanied by MODs in our study. These find-
ings are consistent with study of Leo et al. [12]. Addition-
ally, died patients were admitted on day five of illness and
most of them had defervescence, followed by rapid deteri-
oration of clinical condition. Our observation is consistent
with an earlier study done on dengue deaths where late
hospitalization was found to be a possible contributing
factor to increased risk of mortality [17].
In current study, patients were managed according to
their clinical conditions. Hydration status was maintained
either by oral or intravenous routes. Patients were treated
with acetaminophen and H2 receptors blockers/proton
pump inhibitors for fever and gastrointestinal disturbances,
respectively. Twenty three (3.9 %) patients with DF and 16
(23.3 %) patients with DHF received blood transfusion in
our study. Most of the patients were fully recovered at
discharge but hepatic and renal anomalies were present in
35.5 % and 12.1 % patients respectively (Table 5).
Conclusions
Dengue viral infection is a dangerous and debilitating
disease that is a growing threat to the global health.
Malaysia is facing worse dengue crisis where death toll
due to dengue have raised to danger level. Our findings
showed that dengue is common in all age groups regard-
less of gender, race and residency. In current study,
dengue presented with several typical and some atypical
manifestations. Our data showed that DF and DHF
presented with significantly different clinico-laboratory
characteristics where DHF is fatal and highly morbid
disease accompanied by multiple organ dysfunctions and
longer hospital stay. Presence of age > 40 years, sec-
ondary infection, diabetes mellitus, lethargy, thick
gallbladder and delayed hospitalization can predict
high risk patients for developing DHF. Understanding
the predictor of DHF/DSS development would pro-
vide information to identify individuals at higher risk
and on the other hand, give sufficient time to clini-
cians for reducing dengue related morbidity and
mortality. Routine use of laboratory values in diagno-
sis of dengue coupled with public awareness and
vigilant monitoring by health care professionals could
go a long way in combating dengue. Our findings will
help national dengue control authorities to continue
strive for prevention and treatment of highly incident
and dangerous tropical disease such as DVI.
Abbreviations
AG ratio: Albumin globulin ratio; AKI: Acute kidney injury; ALP: Alkaline
phosphatase; ALT: Alanine amino transferase; ALT: Alanine aminotransferase;
aPTT: activated prothrombin time; AST: Aspartate aminotransferase;
BPM: Beats per minute; BUN: Blood urea nitrogen; CHF: Congestive heart
failure; CKD: Chronic kidney disease; DF: Dengue fever; DHF: Dengue
hemorrhagic fever; DM: Diabetes mellitus; DSS: Dengue shock syndrome;
Page 11 of 12
DVI: Dengue viral infection; Hct: Hematocrit; HPL: Hyperlipidemia;
HTN: Hypertension; IHD: Ischemic heart disease; INR: International normalized
ratio; MAP: Mean arterial pressure; PT: Prothrombin time; SCr: Serum
creatinine; ULN: Upper limit normal; WBCs: White blood cells.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
THM: conception, design of study, data analysis and interpretation, AHK:
study supervision and revising manuscript, AS: study supervision and revising
manuscript for intellectual contents, ASA: approval of final draft and revising
manuscript for intellectual contents, YKH: data acquisition and drafting of
manuscript, FJ: Data acquisition and statistical analysis. All authors read and
approved the final manuscript.
Acknowledgement
We are thankful to Institute of Postgraduate Studies (IPS) of University Sains
Malaysia (USM) for fellowship support [Ref. no. P-FD0010/149(R)].
Author details
1
Discipline of Clinical Pharmacy, School of Pharmaceutical Sciences,
University Sains Malaysia, Penang 11800, Malaysia. 2Chronic Kidney Disease
Resource Centre, School of Medical Sciences, Health Campus, University
Sains Malaysia, Kubang Kerain 16150, Kelantan, Malaysia. 3Department of
Obstetrics and Gynecology, School of Medical Sciences, Health Campus,
University Sains Malaysia, Kubang Kerain 16150, Kelantan, Malaysia.
Received: 12 May 2015 Accepted: 22 September 2015
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